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1.  Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children 
The New England journal of medicine  2016;374(26):2519-2529.
Background
The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.
Methods
We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child’s home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group.
Results
Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], −17.0 to 21.9; P = 0.66) in the intention-to-treat analysis and 7.0% (95% CI, −14.5 to 24.6; P = 0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P = 0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: −43.5%; 95% CI, −100.3 to −2.8 [P = 0.03]; per-protocol analysis: −56.8%; 95% CI, −118.7 to −12.3 [P = 0.008]).
Conclusions
A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.)
doi:10.1056/NEJMoa1515257
PMCID: PMC4962898  PMID: 27355532
2.  Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease 
The New England journal of medicine  2016;374(26):2553-2562.
BACKGROUND
Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments.
METHODS
We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture.
RESULTS
In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect.
CONCLUSIONS
Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss National Foundation and the National Institutes of Health.)
doi:10.1056/NEJMoa1509342
PMCID: PMC5070790  PMID: 27355534
3.  Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis 
The New England journal of medicine  2010;363(12):1117-1127.
Background
Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.
Methods
We conducted a phase 1–2 trial of INCB018424 in patients with JAK2 V617F–positive or JAK2 V617F–negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis.
Results
A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.
Conclusions
INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed.
doi:10.1056/NEJMoa1002028
PMCID: PMC5187954  PMID: 20843246
5.  Reducing Diagnostic Errors — Why Now? 
The New England journal of medicine  2015;373(26):2491-2493.
doi:10.1056/NEJMp1508044
PMCID: PMC4943217  PMID: 26397948
6.  A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms 
Ménard, D. | Khim, N. | Beghain, J. | Adegnika, A.A. | Shafiul-Alam, M. | Amodu, O. | Rahim-Awab, G. | Barnadas, C. | Berry, A. | Boum, Y. | Bustos, M.D. | Cao, J. | Chen, J.-H. | Collet, L. | Cui, L. | Thakur, G.-D. | Dieye, A. | Djallé, D. | Dorkenoo, M.A. | Eboumbou-Moukoko, C.E. | Espino, F.-E.-C.J. | Fandeur, T. | Ferreira-da-Cruz, M.-F. | Fola, A.A. | Fuehrer, H.-P. | Hassan, A.M. | Herrera, S. | Hongvanthong, B. | Houzé, S. | Ibrahim, M.L. | Jahirul-Karim, M. | Jiang, L. | Kano, S. | Ali-Khan, W. | Khanthavong, M. | Kremsner, P.G. | Lacerda, M. | Leang, R. | Leelawong, M. | Li, M. | Lin, K. | Mazarati, J.-B. | Ménard, S. | Morlais, I. | Muhindo-Mavoko, H. | Musset, L. | Na-Bangchang, K. | Nambozi, M. | Niaré, K. | Noedl, H. | Ouédraogo, J.-B. | Pillai, D.R. | Pradines, B. | Quang-Phuc, B. | Ramharter, M. | Randrianarivelojosia, M. | Sattabongkot, J. | Sheikh-Omar, A. | Silué, K.D. | Sirima, S.B. | Sutherland, C. | Syafruddin, D. | Tahar, R. | Tang, L.-H. | Touré, O.A. | Tshibangu-wa-Tshibangu, P. | Vigan-Womas, I. | Warsame, M. | Wini, L. | Zakeri, S. | Kim, S. | Eam, R. | Berne, L. | Khean, C. | Chy, S. | Ken, M. | Loch, K. | Canier, L. | Duru, V. | Legrand, E. | Barale, J.-C. | Stokes, B. | Straimer, J. | Witkowski, B. | Fidock, D.A. | Rogier, C. | Ringwald, P. | Ariey, F. | Mercereau-Puijalon, O.
The New England journal of medicine  2016;374(25):2453-2464.
BACKGROUND
Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)–propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale.
METHODS
We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci.
RESULTS
We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas — one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China — with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay.
CONCLUSIONS
No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral.
doi:10.1056/NEJMoa1513137
PMCID: PMC4955562  PMID: 27332904
7.  Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma 
The New England journal of medicine  2016;374(25):2419-2429.
Background
We tested interim positron-emission tomography–computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin’s lymphoma.
Methods
Patients with newly diagnosed advanced classic Hodgkin’s lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.
Results
A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin’s lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.
Conclusions
Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.)
doi:10.1056/NEJMoa1510093
PMCID: PMC4961236  PMID: 27332902
8.  An Integrated View of Potassium Homeostasis 
The New England journal of medicine  2015;373(18):1786-1787.
doi:10.1056/NEJMc1509656#SA2
PMCID: PMC5177965  PMID: 26510041
9.  Abatacept in B7-1–Positive Proteinuric Kidney Disease 
The New England journal of medicine  2014;370(13):1263-1266.
SUMMARY
Abatacept (cytotoxic T-lymphocyte–associated antigen 4–immunoglobulin fusion protein [CTLA-4–Ig]) is a costimulatory inhibitor that targets B7-1 (CD80). The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens. Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. Our data indicate that abatacept may stabilize β1-integrin activation in podocytes and reduce proteinuria in patients with B7-1–positive glomerular disease.
doi:10.1056/NEJMc1400502
PMCID: PMC5176021  PMID: 24670178
10.  Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma 
The New England journal of medicine  2016;374(14):1344-1355.
BACKGROUND
Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results.
METHODS
We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy.
RESULTS
A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival.
CONCLUSIONS
In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.)
doi:10.1056/NEJMoa1500925
PMCID: PMC5170873  PMID: 27050206
11.  Elimination of Taenia solium Transmission in Northern Peru 
The New England journal of medicine  2016;374(24):2335-2344.
BACKGROUND
Taeniasis and cysticercosis are major causes of seizures and epilepsy. Infection by the causative parasite Taenia solium requires transmission between humans and pigs. The disease is considered to be eradicable, but data on attempts at regional elimination are lacking. We conducted a three-phase control program in Tumbes, Peru, to determine whether regional elimination would be feasible.
METHODS
We systematically tested and compared elimination strategies to show the feasibility of interrupting the transmission of T. solium infection in a region of highly endemic disease in Peru. In phase 1, we assessed the effectiveness and feasibility of six intervention strategies that involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. In phase 2, we compared mass treatment with mass screening (each either with or without vaccination of pigs) in 17 villages. In phase 3, we implemented the final strategy of mass treatment of humans along with the mass treatment and vaccination of pigs in the entire rural region of Tumbes (107 villages comprising 81,170 people and 55,638 pigs). The effect of the intervention was measured after phases 2 and 3 with the use of detailed necropsy to detect pigs with live, nondegenerated cysts capable of causing new infection. The necropsy sampling was weighted in that we preferentially included more samples from seropositive pigs than from seronegative pigs.
RESULTS
Only two of the strategies implemented in phase 1 resulted in limited control over the transmission of T. solium infection, which highlighted the need to intensify the subsequent strategies. After the strategies in phase 2 were implemented, no cyst that was capable of further transmission of T. solium infection was found among 658 sampled pigs. One year later, without further intervention, 7 of 310 sampled pigs had live, nondegenerated cysts, but no infected pig was found in 11 of 17 villages, including all the villages in which mass antiparasitic treatment plus vaccination was implemented. After the final strategy was implemented in phase 3, a total of 3 of 342 pigs had live, nondegenerated cysts, but no infected pig was found in 105 of 107 villages.
CONCLUSIONS
We showed that the transmission of T. solium infection was interrupted on a regional scale in a highly endemic region in Peru. (Funded by the Bill and Melinda Gates Foundation and others.)
doi:10.1056/NEJMoa1515520
PMCID: PMC4962610  PMID: 27305193
12.  Early Performance of Accountable Care Organizations in Medicare 
The New England journal of medicine  2016;374(24):2357-2366.
BACKGROUND
In the Medicare Shared Savings Program (MSSP), accountable care organizations (ACOs) have financial incentives to lower spending and improve quality. We used quasi-experimental methods to assess the early performance of MSSP ACOs.
METHODS
Using Medicare claims from 2009 through 2013 and a difference-in-differences design, we compared changes in spending and in performance on quality measures from before the start of ACO contracts to after the start of the contracts between beneficiaries served by the 220 ACOs entering the MSSP in mid-2012 (2012 ACO cohort) or January 2013 (2013 ACO cohort) and those served by non-ACO providers (control group), with adjustment for geographic area and beneficiary characteristics. We analyzed the 2012 and 2013 ACO cohorts separately because entry time could reflect the capacity of an ACO to achieve savings. We compared ACO savings according to organizational structure, baseline spending, and concurrent ACO contracting with commercial insurers.
RESULTS
Adjusted Medicare spending and spending trends were similar in the ACO cohorts and the control group during the precontract period. In 2013, the differential change (i.e., the between-group difference in the change from the precontract period) in total adjusted annual spending was −$144 per beneficiary in the 2012 ACO cohort as compared with the control group (P = 0.02), consistent with a 1.4% savings, but only −$3 per beneficiary in the 2013 ACO cohort as compared with the control group (P = 0.96). Estimated savings were consistently greater in independent primary care groups than in hospital-integrated groups among 2012 and 2013 MSSP entrants (P = 0.005 for interaction). MSSP contracts were associated with improved performance on some quality measures and unchanged performance on others.
CONCLUSIONS
The first full year of MSSP contracts was associated with early reductions in Medicare spending among 2012 entrants but not among 2013 entrants. Savings were greater in independent primary care groups than in hospital-integrated groups.
doi:10.1056/NEJMsa1600142
PMCID: PMC4963149  PMID: 27075832
13.  Four-Year Efficacy of RTS,S/AS01E and Its Interaction with Malaria Exposure 
The New England journal of medicine  2013;368(12):1111-1120.
Background
The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited.
Methods
For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child’s exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria.
Results
Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P = 0.005) and 32.1% (95% CI, 11.6 to 47.8; P = 0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, −8.6 to 36.3; P = 0.18) and 24.3% (95% CI, 1.9 to 41.6; P = 0.04), respectively, calculated by the Andersen–Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P = 0.004) and with increasing exposure to malaria (P = 0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was −0.4% (95% CI, −32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, −11.0 to 36.4).
Conclusions
The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.)
doi:10.1056/NEJMoa1207564
PMCID: PMC5156295  PMID: 23514288
14.  Genomic Classification and Prognosis in Acute Myeloid Leukemia 
The New England journal of medicine  2016;374(23):2209-2221.
Background
Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice.
Methods
We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes.
Results
We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2R172 mutations (in 1%). Patients with chromatin–spliceosome and TP53–aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene–gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials.
Conclusions
The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.)
doi:10.1056/NEJMoa1516192
PMCID: PMC4979995  PMID: 27276561
15.  Exome Sequencing and the Management of Neurometabolic Disorders 
The New England journal of medicine  2016;374(23):2246-2255.
BACKGROUND
Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level.
METHODS
To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes.
RESULTS
We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).
CONCLUSIONS
Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)
doi:10.1056/NEJMoa1515792
PMCID: PMC4983272  PMID: 27276562
16.  Coronary-Artery Bypass Grafting 
doi:10.1056/NEJMc1608042#SA2
PMCID: PMC5135735  PMID: 27602685
17.  Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand 
The New England journal of medicine  2016;374(22):2120-2130.
Background
Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure.
Methods
We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly.
Results
Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits.
Conclusions
The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.)
doi:10.1056/NEJMoa1508952
PMCID: PMC5111628  PMID: 27192360
18.  Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis 
The New England journal of medicine  2012;367(2):115-123.
BACKGROUND
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known.
METHODS
We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo.
RESULTS
Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum.
CONCLUSIONS
KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.)
doi:10.1056/NEJMoa1110740
PMCID: PMC5131800  PMID: 22784115
19.  The impact of removing Planned Parenthood from Texas Women’s Health Program 
The New England journal of medicine  2016;374(9):853-860.
BACKGROUND
Fifteen states bar or propose to bar Planned Parenthood affiliates from providing health care services with public funds. After courts blocked exclusion from the Texas Medicaid fee-for-service family planning program, on January 1, 2013, Texas excluded Planned Parenthood from a state-funded replacement program. We assessed contraceptive method provision, method continuation through the program, and Medicaid-paid deliveries before and after the Planned Parenthood exclusion.
METHODS
Using all claims under Texas’ fee-for-service family planning programs in 2011 – 2014, we examined change in contraceptive provision by method before and after the Planned Parenthood exclusion. For injectable contraceptive users at baseline, we observed contraceptive continuation through the program and Medicaid-paid deliveries. We used difference-in-differences to compare changes in outcomes between counties with and without Planned Parenthood clinics.
RESULTS
Following the Planned Parenthood exclusion, there was a 35% (369/1040) decline (p<0.001) in provision of long-acting reversible contraceptive methods, a 31% (2123/6832) decline (p<0.001) in use of injectable contraceptives; there was no significant change in the use of short-acting hormonal contraceptive methods. Among users of injectable contraceptives, there was 22% lower contraceptive continuation in the program (p<0.001) following the exclusion, and an additional 1.9% of women (27% increase) had Medicaid-paid deliveries within 18 months (p=0.014).
CONCLUSIONS
Texas’s exclusion of Planned Parenthood from a state-funded replacement for a Medicaid fee-for-service program was associated with adverse changes in provision of contraception, and for injectable contraceptive users, a decline in contraceptive continuation through the program and an increase in Medicaid-paid deliveries. (Funded by the Susan T. Buffett Foundation.)
doi:10.1056/NEJMsa1511902
PMCID: PMC5129844  PMID: 26836435
20.  Diacetylmorphine versus Methadone for the Treatment of Opioid Addiction 
The New England journal of medicine  2009;361(8):777-786.
BACKGROUND
Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.
METHODS
In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index.
RESULTS
The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P<0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients).
CONCLUSIONS
Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.)
doi:10.1056/NEJMoa0810635
PMCID: PMC5127701  PMID: 19692689 CAMSID: cams373
21.  Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer 
The New England journal of medicine  2012;367(19):1783-1791.
Background
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.
Methods
We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.
Results
Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of adverse events of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesia were higher with lapatinib plus capecitabine.
Conclusions
T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann–La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.)
doi:10.1056/NEJMoa1209124
PMCID: PMC5125250  PMID: 23020162
22.  Postmenopausal Osteoporosis 
The New England journal of medicine  2016;374(21):2095-2097.
doi:10.1056/NEJMc1602599
PMCID: PMC5104560  PMID: 27223158 CAMSID: cams6243
23.  Life Expectancy after Myocardial Infarction by Hospital Performance 
The New England journal of medicine  2016;375(14):1332-1342.
Background
Thirty-day risk-standardized mortality rates after acute myocardial infarction are commonly used to evaluate and compare hospital performance. However, it is not known whether differences between hospitals in early patient survival are associated with differences in long-term survival.
Methods
We analyzed data from the Cooperative Cardiovascular Project, a study of Medicare beneficiaries hospitalized for acute myocardial infarction between 1994-96 with 17 years of follow-up. We grouped hospitals into five strata based on case-mix severity. Within each case-mix stratum, we compared life expectancy in patients admitted to high and low-performing hospitals, as defined by quintiles of thirty-day risk-standardized mortality rates. Cox proportional hazards models were used to calculate life expectancy.
Results
The study sample included 119,735 patients with acute myocardial infarction admitted to 1,824 hospitals. Within each case-mix stratum, survival curves for patients admitted to hospitals in each risk-standardized mortality rate quintile separated within the first 30 days and then remained parallel over 17 years of follow-up. Estimated life expectancy declined as hospital risk-standardized mortality rate quintile increased. On average, patients treated at high-performing hospitals lived between 1.14 and 0.84 years longer than patients treated at low-performing hospitals, depending on hospital case-mix. When 30-day survivors were examined separately, there was no difference in unadjusted or adjusted life expectancy across hospital risk-standardized mortality rate quintiles.
Conclusion
Patients admitted to high-performing hospitals after acute myocardial infarction had longer life expectancies than patients treated in low-performing hospitals. This survival benefit arose in the first 30 days and persisted over the long term.
doi:10.1056/NEJMoa1513223
PMCID: PMC5118048  PMID: 27705249
24.  Danazol Treatment for Telomere Diseases 
The New England journal of medicine  2016;374(20):1922-1931.
BACKGROUND
Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.
METHODS
In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.
RESULTS
After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively.
CONCLUSIONS
In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)
doi:10.1056/NEJMoa1515319
PMCID: PMC4968696  PMID: 27192671

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